SMM & MGUS: clinical relevance, the PROMISE study & the role of genomics

Dr Francesco Maura: Good morning. My name is Francesco Maura from University of Miami, Sylvester Comprehensive Cancer Center, and I’m here with Dr O’Donnell and we are both attending the IBC 2024 conference, where we will discuss several precursor conditions of a hematological tumors, in particular chronic lymphocytic leukemia, myeloid tumors and multiple myeloma, and today we are talking about multiple myeloma specifically. So, we know that multiple myeloma has two main precursor conditions, one called monoclonal gammopathy of undetermined significance, or MGUS, and one is called smoldering multiple myeloma. The differentiation between these two entities is actually pretty old, we’re talking about the 80s, where, you know, giants of hematology like Dr Bob Kyle defined a threshold of 10% plasma cell to differentiate the two. The MGUS have a lower risk of progression compared to the smoldering, but it’s clear that today the 10% threshold is starting to be a little bit, uncomfortable for clinicians and for doctors because it’s clear that some MGUS progresses to multiple myeloma, while most are stable, and smoldering is much more heterogeneous.

So the idea that we have, I think, as a field is that there are actually two different entities. One is benign and one is malignant, and the malignant could be at imminent risk of progression, so what we could call today smoldering high-risk and others are at a lower risk of progression but this is still cancer, so it means that it will progress a certain point, but maybe not in the first two years of follow- up.

So of course, differentiating these two entities is still a challenge, we don’t have yet all the knowledge and that’s why we are meeting to discuss this and that’s why a lot of our colleagues are doing important studies, like the PROMISE study.
So maybe you can mention something about one of the few screening studies in the world currently on precursor conditions in myeloma.

Dr Elizabeth O’Donnell: Sounds great. So I think this is a unique conference in that it’s not limited to plasma cell precursors, but it is limited to precursor conditions. So in this conference, we really look across different blood cancers at these unique states that we can identify that may have high risk of evolution or may in fact be benign, and much of the focus of this conference, and specifically the PROMISE study, which I will talk about, is really how do we detect these precursor conditions? How do we then risk stratify these precursor conditions to get at what you were just talking about? Are there indolent varieties versus higher risk of progression varieties? And finally, when we do identify a high-risk profile, what do we do about that? What interventions are appropriate? Or maybe some people would ask, are interventions appropriate? So these are some of the topics that we hope to cover in a lot of detail over the next couple of days.

At Dana-Farber, we’re leading the PROMISE study, which is a screening study that looks specifically at high-risk populations that have been identified as those who are African American or of African descent, and also those who have strong family history, either first degree family members with plasma cell dyscrasias or those who have two or more first or secondary relatives who have either a hematologic malignancy or any type of plasma cell disorder. And so the ambition of this study is to enroll about 30,000 patients, and it’s almost halfway there. It has expanded to include a cohort from South Africa as well. And really, what we’re seeing when we use a different technique, so historically we use serum protein electrophoresis to quantify monoclonal protein, here in this study we use mass spectrometry, which has given us an insight that we can actually pick up an even earlier disease state, something we’ve coined monoclonal gammopathy of indeterminate potential, so an even earlier stage, and it’s also a little bit more sensitive for quantifying these other early, monoclonal bands.

And so we’ll talk about that and we’ll talk about the implications of screening. Should we be doing it and for whom? You know, we know that screening does help to prevent cancers, but we know that not every cancer has an indicated reason for screening. So are there specific populations like we see in prostate cancer where we may preferentially screen? So that’s one of the really exciting things that we’ll be talking about.

And then also we’ll be talking about biology, some of the genetic considerations, which I think you’re probably better suited to talk about than I, in terms of precursor disease.
And then finally about interventions and how what are the right interventions and for whom?

Dr Francesco Maura: Yeah, I think that also the important aspect of the PROMISE study for the community is that it’s mostly focused on the peripheral blood, which, of course, is what a lot of patients are looking for. Right now, the certification and definition of MGUS and smoldering myeloma is based on the number of plasma cells in the bone marrow. So I need to look at the bone marrow, which means I need to do an invasive biopsy which is expensive, which is invasive, requires local anesthesia, and even if it’s not associated with any particular complications and it’s usually well tolerated in general, patients don’t want it and it’s questionable to perform bone marrow right now, for example, for MGUS.

So I think that the idea, outside of clinical trials, is to explore, non-invasive strategies like the PROMISE. It’s clearly an important step forward for the research. Then of course, the question is, once you do ultra-sensitive technology to identify monoclonal gammopathy, are these the ways to do it in the population or is just like a standard SPEP is what we probably need?
I think that from the clinical standpoint, like SPEP is probably just fine to, you know, screen, but I think from the biological standpoint, it’s very important, the PROMISE [study] is looking for the more ultra-sensitive approaches. I don’t know, what’s your opinion about that?

Dr Elizabeth O’Donnell: Yeah, I think you have to have kind of a pragmatic approach as well. So is everybody going to have access to the technology? We know that may take time to evolve, but what I think is useful when you have a study, you can make generalizations for the overall population using available modalities. But the other piece of this study is the ability to do the science as well.
So we can take what we learn through more sensitive technology. So not only are we looking at the prevalence of MGUS using different technologies, but we’re looking at people over time to understand the evolution of disease, and by serially banking specimen, we can then either… we can retrospectively and then potentially prospectively look at specific alterations that may confer a higher risk.

That’s also paired with clinical data. So are there features whether they be genomic, immunologic, or clinical, that we can put together and create a kind of a polygenic risk score or other factors which we think can then bring out to a broader population, but we could probably still use available technologies on a screening level.

Dr Francesco Maura: Yeah, and I, you know, moving forward, I think the idea that we can detect these monoclonal proteins, you know, we know for a long time we have just now better technology and better understanding of why this clone happened to be in the blood; associated with aging, associated with certain environmental factors in a certain population. But I think it’s important to not just identify them, and that’s also what the problem is doing, but also try to understand once you identify, is that a benign condition or not? And because most of these are very early, you know, in time, in particular if you screen, you will see more and more what we would call today MGUS or low-risk smoldering. But those are, you know, because we screen, we detect them earlier. A lot of these are probably what we would see as a high-risk or multiple myeloma.

So I think, in this context, the idea to have genomic markers that can identify the tumor transformation of these plasma cells or B-cells before the clonal expansion, I think it’s going to be very important. And the reason is that it’s quite logical; if a tumor grows because it accumulates genomic alterations one after the other, usually across, according to our estimates myeloma takes three decades on average to develop, so it’s like a progressive accumulation alteration. If you have a transformation, the transformation always precedes the expansion. So in the moment in which you have more than 10% plasma cells or 60% plasma cells, it is because you acquire certain alterations that make that possible. And so the identification of this alteration through different technology, that could be, I think, at the beginning, we should still rely on invasing payer or non-invasive. I’m particularly fond of the work from Dana-Farber and Irene on circulating plasma cells, secreting plasma cells, but I think genomics will be the answer and will replace most of the current risk criteria.

So now the question, of course, and, you know, Dana-Farber is probably the center leading with the largest number of clinical trials on smoldering, what to do once we recognize these patients? And, of course, I think we are not yet there, and so there is a lot of controversies if we should treat or not treat smoldering, but also which should be the criteria for treating smoldering, because looking at clinical trials, I have clinical trials where you just need the one cue to be treated and clinical trials where you have very stringent criteria that you need to be like very high-risk, like ENW 2020 or other, you know, very, stringent criteria.

So, you know, the pattern that I see is that a lot of academic centers are developing single center clinical trials with a very broad criteria of enrolment, and I’m not sure, and I don’t have a strong opinion, but I’m not sure if that’s what we really need, because a lot of these patients will probably not progress.

Dr Elizabeth O’Donnell: And I think these are the critical questions. And we actually have the FDA here at this meeting, and I think this is an opportunity to think about our clinical trial design. Cancer and cancer science is changing rapidly, and so, you know, what tools we have now will probably not be the more relevant ones five years from now. One of the issues, though, in terms of risk stratification, is the broader applicability to old data then as well, where it wasn’t performed. So what do we know? What’s our current state of knowledge?

So there have been two randomized prospective studies demonstrating the benefit of early intervention. Both of those use the agent lenalidomide. The Spanish group published this data many years ago in the New England Journal, showing both a progression-free and overall survival benefit. We then had the ECOG study of lenalidomide, and again saw a benefit in progression-free survival. But most of the trials beyond that have been single arm studies. And so that’s a challenge as well where you don’t have a comparator arm. We know that the regimens being put together are highly efficacious. There are some of our best myeloma drugs being used in an earlier setting, which is intuitive, right? So if we have effective therapies that we use in people once they’ve already been diagnosed and have symptomatic disease, perhaps we can use them earlier.

But the question then becomes is it curative earlier? You know, do we actually cure plasma cell dyscrasias at any point in early intervention? And if you’re going to introduce them, who are the correct patients as well? And then the question of what regimen to choose? Is less, more? Is less more for certain individuals? If you have an older patient who has high-risk smoldering with other medical comorbidities, is it sufficient to choose something like lenalidomide or dexamethasone with it to put a cap on the disease? Or do you go with a highly aggressive regimen, such as a four drug combination, or even potentially an immunotherapy such as a bispecific T-cell engager or even CAR-T in the right patient?

These are kind of different ends of a spectrum that there’s not even consensus that we should be on a therapeutic spectrum. But I do think, as we develop clinical trials, one of the challenges in interpreting this will be, when you’ve done multiple single-arm studies at single institutions, how can you interpret the data in a way that becomes broadly applicable to different populations?

And so, you know, I hope through the course of this meeting year after year, these are the types of questions that I feel like we’re giving the right type of thought to. We have a meeting of individuals who all are stakeholders in this, wanting to do the right thing and wanting to engage the right parties. We also have Phil Castle from the NCI here. So really trying to hear not only from the experts within this field, but the experts in prevention and screening and the FDA in terms to how best to develop the right programs so that we can answer the important questions and ultimately deliver patients the greatest benefit in terms of the therapies that we choose.

Dr Francesco Maura: So I want to add that the trials that have been done, the randomized Phase III trials, the problem with smoldering is that the classification also changes. So for example, in the Spanish, which was extremely, I would say, pioneering in the design and the ambition to treat smoldering in a randomized trial and was published in 2013, the first paper from Mari-Vi Mateos, and since then there is only one randomized trial published in 2020. So it’s kind of like more than ten years ago, and that was still the main randomized trial in smoldering, it was kind of impressive how they were able to develop that. But at the same time, for the criteria of that time, a lot of what were called smoldering are now called multiple myeloma, so that probably may overinflate the advantage of early treatment, as well as the ECOG study.

I think PFS is definitely an important endpoint, but it always depends on what’s the aim, if the aim is the cure or just delaying the treatment. And so it’s delaying the treatment, I think it’s also important to show the second treatment PFS, to see if the disease was more aggressive due to the therapy or in general, overall survival, even if you don’t rely on that necessarily, but I think these are important.

But I think that because the sample size of all these trials, for obvious reasons, it’s always difficult, and that’s why most of the people do Phase II or Phase I in a single institution. The key for the interpretation of the studies and to understand why these studies are useful,
and a lot of people who are critics about smoldering trials say that these studies are useless, I think they are not if they’re properly analyzed and properly put into context. And I think an example is the E-PRISM study, published by Irene Ghobrial in Cancer Cell, where, together with the Phase II trial where patients were treated with elotuzumab, lenalidomide, and dexamethasone, there was also a very comprehensive, detailed biological translational study. And we have currently in press also a study where we did the same analysis on the NIH study with KRd, smoldering with KRd, with a very high rate of MRD negativity. And the Spanish presented at the last International Myeloma Society conference, as an oral communication, their study, GEM-CESAR, where patients were treated with KRd plus transplant for high-risk smoldering.

So the translational studies and all these data are pretty consistent in showing that the population we enroll in the smoldering trials is not high-risk myeloma. And now most of these patients are actually very indolent, so they may be high-risk myeloma, they might progress to myeloma, but they represent the favorable myeloma. And so we don’t see that kind of high-risk myeloma or the genomic complexity that is classic for myeloma. So the question is, is it because we treat earlier or is because we select a population of smoldering that is indolent and gives us enough time?

I think that a lot of aggressive disease, unfortunately, the progression from MGUS or being detectable to myeloma, it’s very quick, and so probably we don’t enroll because patients don’t have time to get into follow-up, to get screened, and to get treated like, you know, MAF, or TP53, or 1Q amp, all these very aggressive myeloma, I think they just progress very fast and so that’s why we don’t have in any of these trials these patients. And that, of course, is a challenge because it means that we need to check these events in the MGUS probably, in particular in the screening settings. And then this also means that if you have those high-risk features, even if you have a low disease, you should monitor or maybe treat early because then the disease is going to be particularly aggressive later.

It’s very complicated, but I think that the key for Phase II/Phase I studies, and even for Phase III smoldering, is really put each single patient in the context of their genomic complexity or simplicity to interpret the data. You can say that smoldering are cured, or 70% MRD-negativity at ten years, like the NIH study, but then most of the patients were actually very indolent.

Dr Elizabeth O’Donnell: But that’s through the retrospective lens, and I think where we have to bring this back, a lot of the data that you’ve cited is looking at things retrospectively, and so part of the goal of this conversation is to think about how we target this to a broad population of practicing hematologists and oncologists.

So when you look at the Spanish study comparing, lenalidomide and dexamethasone with observation, part of the reason that that was not adopted into practice was that the modality used for imaging in that study was the skeletal survey, which probably is not the most sensitive means by which we detect bone lesions. So many of those patients may actually have had myeloma at the time. So that’s part of the issue with that.

But we can’t go back in time, so we have to think about what are we doing in the current state. And we have to be careful when we talk about all of these genomic criteria and smaller criteria, that we are aware that the vast population or the majority of the population, not only nationally but globally, will not have access to these techniques. And so we don’t want to delay progress in the name of perfection, so we have to come up with strategies that are obviously evidence-based, thoughtfully planned, but we also have to recognize the need to move the field forward. And so I think using techniques for screening, identifying high-risk populations, as we’re doing, not only on a population base, which we’re seeing in the in the iSTOP myeloma study, but on a risk-based screening are important steps forward that people on a national and international level can participate in.

I think as we start to clarify this question of who is indolent versus who is high-risk, hopefully we will come up with tools that can be readily transmitted into common practice. But we do have to recognize, and I think a lot is changing in terms of blood-based biopsy, it’s not only going to be in plasma cell dyscrasias where we already have the ability to screen people’s blood, but as we think about new technologies that are evolving for blood-based biopsy, what does that mean for screening in general?

And when we look at cure rates, even though we’ve made tremendous benefit in the types of therapeutics that we’re able to offer patients with myeloma, there is no true cure. There may be a tail on the curve where we think we may be carrying some people, but in general, when we can find disease earlier in solid tumors, it equates to greater chance of cure. That may or may not be true in plasma cell dyscrasias, but we always have to keep that in our focus. What is the reason we’re doing this? What is the goal of this work? And so I think, you know, we’re making the right steps, we’re pulling in the right people, and I hope the goal of the work in the next couple of years will be to think about trial design that is not only able to include… remember, smoldering myeloma is caught incidentally for the most part, and so you’re never going to be able to do, as you mentioned, the big studies that we do for the validation of other studies based on the numbers. So that’s a challenge to begin with, even as a workaround.

And so you’re starting from limitations. Recognizing those limitations: what are the appropriate endpoints? So is MRD the right endpoint? Is it an acceptable endpoint that we use when we’re trying to design studies so that we can say we demonstrated we know that MRD in is associated with increased progression-free survival in myeloma, so we’re going to make that same assumption, is one approach that’s being used. But I think we have to be careful about the endpoints that we choose so that they have broad reproducibility and applicability not only in academic practice, but in practices for people both in the United States and also internationally, so that we can offer the greatest benefit to the greatest number.

Dr Francesco Maura: So I agree, the only concern that I have, and that’s why I think the smoldering trials that report outcome data should also be paired with a more comprehensive genomic profiling in the first publication, not in the follow-up paper, like the E-PRISM, I think is the example of how the smoldering trials should be published and developed.

My impression and the data that I have from E-PRISM, the Spanish, and the KRd, is that in around half of the patients we enroll in these trials were not myeloma. And so I think the criteria we are using are what makes people so concerned and against the treatment with smoldering. So, the idea that I have is of course endpoints are important, but endpoints are also very difficult because if you treat early the PFS is going to be better. All the trials from follicular lymphoma with rituximab to, myeloma, even with thalidomide, like you always get more treatment, better PFS, overall survival in myeloma is going to take 20 years to get, probably you will never see it before you retire. And an MRD, yes, but again if the population that gets the sustained MRD-negativity are the ones that don’t have myeloma, that’s kind of like not great. And the Spanish show that they have ultra-high risk, they call this population ultra-high risk, and they don’t have a great outcome even with the intensification. So I guess the immunotherapy is definitely a good angle for those patients.

But my main concern is that I think that genomics should be integrated also in the enrollment criteria in future clinical trials. We should be more stringent. And so even if the population is going to be smaller for collaborative network and consortium, we can get the same size and the same time of single-center, but we can treat the right population that can really provide information. And it’s fine to do a Phase II trial in a single center, but I think, as Dana-Farber did, you need to provide the genomic correlatives so you can put that population in context, those 50 patients in context. Otherwise, you have the pro-smoldering that will support the great results in MRD negativity of the population that was not even high-risk, or the anti-smoldering that will say that we are treating patients that don’t need treatment. So I think that to really make something that is effective for patients and for the research, we need to be extremely rigorous in the way in which we enroll patients in the trial. And I think genomics can really help, in particular, after several publications that are in the process or have been published already. But of course, that’s challenging. But at the same time, smoldering is not a disease that requires treatment immediately, so you might have time and settings where genomics, even if we are not ready to do them in 24 hours, whole genome sequencing can actually provide some answers. But, you know, of course there is a lot of heterogeneity in opinions in the community, but I guess that’s my personal, maybe not popular, opinion.

Evolution of risk stratification in SMM & MGUS: CTCs & imaging techniques

Dr Shaji Kumar: Hi, I’m Shaji Kumar. I am attending the IBC 2024 meeting here in Lisbon. I would like to introduce my colleagues who are going to be part of the discussion today. This is Dr Bruno Paiva and Dr Elena Zamagni, and we will be talking about an exciting area today, which is the whole concept of early interception in multiple myeloma and related disorders.

So we have known for a long time that myeloma is always preceded by a monoclonal gammopathy of undetermined significance and also smoldering multiple myeloma. And this offers an opportunity for interception early on in the course of the disease. But the challenge always has been identifying who are the individuals who are going to progress. And a lot of progress has been made, and we have been discussing about the different approaches we can take to identify these patients. And this is an area that is constantly improving, and there’s certainly a lot of new technologies that are coming along.
And you talked about the circulating tumor cells and how we can use that. How do you propose that this would be or how do we use that in the future?

Dr Bruno Paiva: Thank you, Shaji, for bringing that topic. I must say that part of our inspiration and motivation to study in greater detail tumor cells in the peripheral blood, so-called circulating tumor cells, and more generally, CTCs, it was, in fact, by some of your studies. In particular, one that was published, I believe, in 2020/2021, where you analyzed how stable or unstable the risk of patients with smoldering myeloma was over time.
And you were looking mainly to the M protein, as well as the free light chains in the serum, the two markers that are part of the International Myeloma Working Group risk model for smoldering myeloma. And of course, you were not looking longitudinally over time to the amount of tumor burden in the marrow, because, of course, patients were not undergoing serial bone marrow assessments.

Now, looking at that data and knowing the importance of identifying stable versus evolving patterns in biomarkers such as hemoglobin, M protein, eventually, the beta-2 microglobulin also, lesions detected by imaging. We felt that there was probably an unmet need to find a certain amount of tumor burden, a cut-off in the peripheral blood, so that you could add that information onto your well-known prognostic factors. That was the motivation.

Dr Shaji Kumar: That’s great. I mean, clearly, I mean, the 2/20/20 certainly is something that everyone can use. It’s in the clinic, it’s protein, it’s a bone marrow plasma cell percentage test that we do every day. But the problem with the 2/20/20 system is it doesn’t allow us to identify everybody who is going to progress and doesn’t. There are still patients who are considered as low-risk by 2/20/20, but still progress much early on, and high-risk patients who don’t progress.

So the ability to discriminate, I mean, especially if you’re thinking of treating them early, we want to really decrease the number of people to almost none who may be unnecessarily treated. And so I think, you know, certainly the circulating tumor cells are one thing, and you talked about the imaging, I mean, that’s one area that obviously needs, I mean, there is certainly a lot of information, but I think we need to get a lot more information.

Dr Elena Zamagni: Yeah, sure. What new imaging did was to redefine the definition of smoldering myeloma. So this is done and we are all relying on this, so it’s well a very good job that was concluded.

What we can do now is decide which patients should be followed-up by imaging, which smoldering myeloma patients, and maybe which patients are at higher risk to develop a focal lesion or bone disease. So I think that the fields are integrating, so for sure, all the patients without lesions, and that’s of course quite obvious maybe, but patient with a dynamic pattern of smoldering myeloma should be followed-up, in my opinion, because they are at higher risk, as well as patients with maybe high circulating tumor cells. So somehow those different parts are integrating.

So I agree with Bruno. We cannot propose continuous imaging for everyone, as well as we cannot propose bone marrow aspiration for everyone continuously. So we may have an interval between based on circulating biomarkers, and then to go for imaging in definite time points. So things are melting together and are creating a more, let’s say, complete risk stratification model. And we also spoke about dynamic, of course, that’s very important to be added.

Dr Bruno Paiva: May I ask a question to the experts? Because it may well be that for patients with stable biomarkers in the first months, years of assessment, that is probably identifying a smoldering myeloma with a different biology. Probably those patients that reach into almost a flat line of progression after five, ten, 15 years, as we have seen in the curves from Dr Kyle in the New England papers, and in such a way, in those cases, you could eventually fade away in time those assessments.

Dr Shaji Kumar: And that’s a very good point because, again, when you look at this, and that is reflected in our clinical practice too, you know, we generally recommend that patients with smoldering myeloma get evaluated every three months. But if somebody is five years out or ten years out from the diagnosis of smoldering, the risk is same as for monoclonal gammopathy of undetermined significance. So those patients at that point, we tend to watch. Maybe see them every year or every other year. And so definitely that will change over time depending upon…

Dr Elena Zamagni: Once again, it is dynamic. So, of course you can upgrade, but you can also downgrade. So probably one day those patients will be called MGUS, bigger MGUS or something similar, because they don’t have anything about myeloma, truly they are something different. So the biology is still studying those patients, and one day probably we will downgrade those patients in the MGUS group.

Dr Shaji Kumar: Yeah, I think it just highlights again, you know, you’re talking about a real spectrum, right? So at one end we are going to try and keep identifying people whom we need to do something about it before something bad happens. And on the other end, we’re just going to keep identifying people whom we don’t need to do anything at all. Just tell them they’re just the same as the general population. And so that we kind of continue to chip away at both ends of the spectrum, so to speak.

Dr Bruno Paiva: It would be ideal, you know, that we have a project ongoing that is called No More MGUS. It’s primarily focused on MGUS, but the concept applies to smoldering myeloma at those late stages or late years of disease stability. And the acronym of the project is like that. No More MGUS because we truly would like to develop the tools in the laboratory to help you identify those monoclonal gammopathies of no clinical significance, so no longer an undetermined significance, clear separation between clinical and lack of clinical significance.

This is challenging, no doubt, but the field has already contributed a lot towards this concept with the identification of monoclonal gammopathies of renal significance, of neurological significance, thrombosis more recently. So it is possible to really fine tune diagnostics.

Dr Shaji Kumar: …and no future significance. Right?

Dr Elena Zamagni: That would be excellent for sure. And in this regard, so we spoke about, also from a clinical perspective, the value of proteinuria. So all these tools are very simple, nothing to do maybe with high science, but are useful not to misdiagnose, not to make an underestimation, to intercept MGRS, to intercept early amyloidosis. We also have to keep in mind at the same time that in this session we spoke a lot about very, very sophisticated biology that in selected centers should go on to truly understand better, dig better into those patients who are behaving so differently.

Dr Shaji Kumar: And I think one of the points that was made, too, is we are probably not getting the maximum information out of the easily available data, because we generally tend to look at those big chunks, you know, it’s there or it’s not there, but just looking at the patterns and how they interact over time, using more of the artificial intelligence type, approaches might tell us a lot more. Because often in the clinic, if the hemoglobin goes down by 0.1 or 0.2 over time, it doesn’t really register as much as they are still in the normal range. But it could be five different variables all moving in the wrong direction, still within the normal range, but could tell you that somebody is actually going to progress pretty soon.

Dr Bruno Paiva: That is a clear application for the near future, I would suspect, of AI and those kind of related tools.

Dr Elena Zamagni: Probably here it’s more easy because you don’t have the variant of the treatment. So in active myeloma, the problem with AI is that the treatments are becoming old and you are looking at something old. But here without treatment, probably it’s more of a field where it will be more easy.

Dr Shaji Kumar: Well, we are certainly making a lot of progress. I’m sure we’ll be able to get a better picture to the patients as we get all these tools closer to the clinic.

Dr Bruno Paiva: And I do think that another important aspect for that kind of information that’s currently still being generated, how to analyze, integrate, probably relying on AI tools, is not only to improve our prediction of risk of transformation, but also our prediction of if the aim of early interception will be achieved or not, depending on what is the aim. And the aim might be prolonging for a long, long time the development of symptoms, or the aim might be curing, hopefully, but really, to use all the information that is being generated in the field of smoldering myeloma also to that purpose: a patient with these kinds of characteristics may respond well or not to a certain type of early intervention.

Dr Shaji Kumar: Absolutely. So a lot more to come.

Non-drug interventions in SMM/MGUS: diet & lifestyle

Dr Urvi Shah: Hi, I’m Urvi Shah, a hematologist and oncologist on the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and I spoke at the Intercepting Blood Cancer meeting on the topic of non-drug interventions in MGUS and smoldering myeloma. What we do know is patients are very frequently ask questions about diet and lifestyle and whether this played a role in the development or if it could slow progression of their cancer.
And I think that is why it’s an important question with a lower-risk intervention and lower risk of toxicity as well. So from epidemiologic or large scale data sets, in terms of dietary patterns, we do know that there are one study that was published from the EPIC-Oxford cohort looking at dietary patterns showing that vegans and vegetarians had a lower risk of myeloma than meat eaters.

And then another dietary cohort looking at the Nurses Health Study looked at dietary inflammatory patterns and showed that high inflammatory diets were actually associated with increased risk of myeloma in mainly males. More recently this year, we published two papers, one in Leukemia, looking at the NIH-AARP data set, and in this data set, we again looked at different dietary patterns. This study was much larger than the two I discussed already. The two I discussed from the EPIC-Oxford one had 65 myeloma cases that had developed, and the other had over 400 cases.

In our current study from the NIH-AARP, we had over 1,300 myeloma cases. And what we did see is that a healthy plant based dietary index, the patients who followed that or the individuals that followed it at the highest quartile, meaning the highest, likelihood of following that diet compared to the lowest likelihood or quartile one, there was a reduced risk of development of myeloma. We also looked at MGUS, and because MGUS is the precursor, many individuals would like to know whether dietary risk factors are associated or linked to MGUS. While we do know there are many causes, maybe diet could be one of the many causes.

And so we looked at the NHANES data set and this was a case controlled study where we had identified – Previously, other investigators had identified the MGUS cases by screening the large population and found 373 MGUS, and we matched it first to one to controls and showed that sugar sweetened beverages such as both artificially sweetened and naturally sweetened, such as Cola, were associated with about 40 to 60% increased risk of MGUS, whereas whole grains, fruits, and vegetables, were associated with about a 30 to 40% reduced risk of MGUS, suggesting again that dietary factors may play a role in large population data sets.

Another thing we do know about obesity and the risk of progression to myeloma, there are now multiple studies published, and two of them that I discussed, one from the VA data set, showed that patients who were overweight or obese, so had an elevated BMI, were twice as likely to progress to myeloma if they had MGUS and an elevated BMI. And similar findings have been seen in a Mayo Clinic data set as well from the Olmsted County. Knowing this evidence that patients with an elevated BMI are twice as likely to progress, and that diet may play a role through these large epidemiologic and retrospective data sets, we did the NUTRIVENTION trial, which was a 20-patient interventional dietary trial with patients with MGUS and smoldering myeloma with an elevated BMI. We provided them lunch and dinner and guidance for snacks and breakfast and allowed them to eat to satiety, so no calorie restriction, only the diet quality was designed to be a high fiber, plant based diet. So patients ate the diet for three months, which we provide in meals, and we provided coaching for six months, and these patients were followed for a year. Blood, stool and a bone marrow samples were collected at certain time points. What we did see was that there was a high adherence rate to the dietary intervention, and only one patient dropped out, because of non-adherence to the diet, and two patients dropped out due to medical reasons unrelated to it. So we had 20 patients complete the 12 week intervention and 18 patients follow with us up to a year. We enrolled a high proportion of minority patients, about 43%, this is much higher than most trials in this space. And we also saw that, the patients had about a 7 to 8% reduction in BMI at 12 weeks, and this was sustained to a year out on the study as well.

Adherence to the dietary intervention at baseline to unprocessed plant foods was about 20% and this increased to 90% on the intervention and was still high one year out at about 60 to 70%, suggesting again that the patients that made these changes made sustained, long-lasting changes even beyond the intervention period. We then looked at correlatives or biomarkers that we know are associated with progression, such as insulin resistance, adiponectin, leptin. We did see fasting insulin levels significantly reduced and adiponectin and leptin ratio, which is a marker of insulin resistance and high levels, is less insulin resistance actually improves, so adiponectin leptin ratio improved.

We also looked at the microbiome. And as you’ve heard about microbiome diversity meaning the variety of different bacteria in the microbiome, we do see that there was an improvement in microbiome diversity at the end of intervention. But what was interesting was this was sustained again to a year out of the intervention as well, again suggesting that the changes that patients made were able to be long-lasting. We also saw a trend towards an increase in butyrate producers or healthier bacteria in the stool. The next thing we looked at is inflammation and whether there was a change in the immune system. Seven patients had elevated C-reactive proteins when they entered the study, and these levels actually showed a trend towards reduction since there were very few patients with an elevated CRP, it’s not statistically significant. We also saw a reduction in inflammatory cytokines in the majority of patients that lost weight and we also did single-cell RNA sequencing of the bone marrow from baseline to one year and looked at changes. We do see an improvement in classical monocytes and Th1 subsets in the bone marrow and similar findings in the blood too, with a reduction in inflammatory CD16 monocytes and an increase in the CD14 classical monocytes.

We’ve also collaborated with Matteo Bellone laboratory in Italy, and his group has looked at a high fiber diet in a mouse model called the Vk*MYC mouse model, and shown that there is a reduction or a slowing of the progression to myeloma in this mouse model and the median progression-free survival, or the time by which myeloma develops, is double in the mice on the high fiber diet compared to those with the control diet, again suggesting very similarly that dietary changes in this mouse model validates what we’re seeing in the patients.
In the patients, we had two patients on the study who had rising M spikes for about a few years before they went on the study and we do see stabilization of their paraproteins or their M spike on the study, which was statistically significant for these two patients.
So just to summarize, what we do see is we see that patients who are able to adhere to this, we also actually saw an improvement in global health status or quality of life. We see an improvement in metabolic profile, microbiome profile, immune profile and maybe in a subset of patients, a slowing of disease progression trajectory, and this validates the epidemiologic findings and also the in vivo mouse models, suggesting that lower-risk interventions that could improve quality of life and lifestyle could be something beneficial and something that patients should consider thinking about.

And of course, we need to validate this in much larger studies. So we have the NUTRIVENTION-3 study that’s currently enrolling looking at this very similar diet in a randomized study form, and also looking at supplements such as curcumin and algae omega 3 as well, to understand how these supplements and diets intertwine or affect progression.

And then we have the last one, a decentralized study in this space, looking at how different supplements affect the microbiome, and this study is open to enrollment all over the United States, and patients don’t have to come to New York for this, but they can send us stool samples from wherever they are, ship it to us, and we ship them the intervention. And this is in collaboration with the HealthTree Foundation. So for NUTRIVENTION-3 and NUTRIVENTION-2, we’re actively enrolling and if you have patients or if you’re interested, please reach out and we’d be happy to share more details. Thank you.

Early interception in SMM & novel agents being explored

Dr Irene Ghobrial:

Hello, my name is Irene Gabriel. I’m from Dana Farber Cancer Institute, and I’m excited here to be in the Intercepting Blood Cancers Meeting with Omar and Kwee. Omar, do you mind introducing yourself?

Omar Nadeem: Yes, I’m Omar Nadeem, I’m also a physician at the Dana Farber Cancer Institute.

Kwee Yong: Hey, I’m Kwee Yong, I work at University College London in the UK.

Irene Ghobrial: So we just completed two days of discussions on early detection, risk stratification, and early interception across blood cancers, whether it’s myeloma, lymphoma and CLL and myeloid malignancies, especially clonal hematopoiesis. And I guess one question, of course, is should we be diagnosing patients early and should we be intercepting knowing that this is such a controversial area right now? Yeah.

Omar Nadeem: No, I think it was a great meeting, we covered a lot a lot of topics across all the different groups there. But yeah, no, I think there’s so much to learn by, you know, identifying these patients and then following their natural sort of progression in terms of who’s at risk and who isn’t and what other, comorbidities and problems are associated with having a clonal disorder like this, specifically focusing on smoldering myeloma, we had a lot of, interest based on early interception with some of the clinical trials that have already been done, but particularly with some of our newer immunotherapy trials that are showing a lot of promise. So, you know, it starts with identification of these patients, we learn their natural history and then figure out which population benefits more, and that’s what’s happening now.

Irene Ghobrial: Now you’ve presented beautiful data on the natural history of patients and I was interested to see that even though we try to do our best with MRIs and PET CT scans, and many of us say, ‘oh, we can find those patients, we can find, you know, CRAB criteria before it happens.’ Yet your data and the Mayo Clinic data, as well as our data indicates that despite all efforts, patients still have fractures and lytic lesions and we cannot diagnose them early enough. And really, the question is, can we intercept those patients early?

Kwee Yong: Exactly, absolutely. And intercepting and diagnosing them and picking them up through screening is one thing, but actually preventing the organ damage is something else.
So what we have to learn is how to follow them and what investigations to use, how to monitor these patients. And really, although it’s such an exciting time, we have all this new technology, clearly we still don’t understand enough about bone disease in in smoldering myeloma and in myeloma. So I think bone disease is the big, big hurdle, and really we need to try and prevent that. But in treating and intercepting smoldering myeloma, of course we will prevent and avoid patients getting fractures, bone pain, bone morbidity that the real goal is to identify the patients who will benefit most from treatment, and also what which treatment is the best. I mean, your study on immunotherapy and bispecific antibodies is tremendous, it’s a wonderful first step. Are all patients who need treatment suitable for that sort of treatment or are there different treatment modalities and different strategies that we should be considering?
Irene Ghobrial: So maybe putting the end in mind, really thinking about best therapies. And I think most of us will say if I have something that is potentially curative, if I have something that’s really giving me deep remissions with less toxicity and for a very short period of time, then many of us would be willing to take that risk, and not just us, it’s the patients who are willing to take the risk and I think that patient preference is so important compared to what physician preference is, because we’re so, into our dogma of don’t treat until, you know, you have end organ damage. But the patients’ requests from us as we see them in the clinic is don’t wait for me to have end organ damage and fractures. But tell us more about the immunotherapy, because maybe that’s the answer to many of the questions and the potential benefit from early interception.

Omar Nadeem: Yeah, it’s remarkable to see how things have changed in less than 20 years, right? Where when first studies of lenalidomide were started in high-risk smoldering myeloma with essentially the same goal, you know, can you treat these patients early and prevent some of the organ damage that we see? And those were positive studies versus observation and then the myeloma progress with therapeutics has moved on so tremendously over the next decade. And we had so many combination therapies, and then we tried to say if getting a deeper and better response with these combination therapies can lead to cures or prevent progression, even for longer in these patients. And those trials showed pretty good response rates, but, you know, you’re balancing the toxicity at that point and trying to figure out which one of those is best. And then came this immunotherapy era, or in the last five years or so, where we’re seeing amazing results in relapsed/refractory myeloma, and then the natural question was can we bring it early in the patients that are at high risk of progression, where they have a healthier immune system.
And so far we’ve demonstrated as part of this trial that this therapy is not only very, very efficacious with a 100% response rate and 100% MRD negativity rate, but it’s also pretty safe in terms of the toxicities that we’re seeing.

You know, we were all worried about that with all of these approaches in smoldering myeloma, but I would say with a single agent, you know, you’re actually mitigating the disease quite extensively. But at the same time, you know, the rates of CRS, high-grade CRS, we’re not seeing at all. You know, you do see some low-grade CRS, but nothing beyond what you would expect with this agent. And then the risk of infections, which comes up with bispecific antibodies and the way that’s being mitigated is with lower frequency and lower doses over time, fixed duration therapy and doing supportive care such as IVIg, etc. to limit that. But this is just the beginning, right? This was the first trial that sort of studied this, now we’re already moving on to see what’s the right duration, you know, which is the right approach, etc. So I think this is going to change very, very quickly.

Irene Ghobrial: And just for the context, we’re talking about teclistamab, but there are so many other bispecific antibodies. But one antibody, teclistamab, is showing us impressive responses with less toxicity compared to the relapsed/refractory setting, which goes back to your question of the immune setting in smoldering myeloma versus relapsed and how immune cell sequencing that you’ve shown in your studies, and we’ve shown indicates that indeed, the Tcells are less exhausted and much more beneficial to be used for immunotherapy in a smoldering setting, potentially compared to a relapsed setting.
So maybe the best drugs of immunotherapy should be used earlier rather than later.
So we are maybe giving us some of your..

Kwee Yong: Exactly, so it brings us around full circle to understanding the importance of the immune response and the host immunity in controlling and determining the equilibrium in smoldering myeloma. And where this equilibrium is lost is when patients progress to myeloma. And what we’ve done, we’ve looked at the T cells in smoldering myeloma, and indeed they show a skewed differentiation, so they’re obviously responding to antigen and they show evidence of chronic antigen exposure, and they’re skewed differentiation – but they’re still functional. They’re not exhausted. So this may be the ideal setting in which to use immunomodulatory agents immunotherapy and your bispecific antibodies. So I think one of the most exciting concepts is the idea of fixed duration, being able to eradicate the clone and getting deep, sustainable, durable MRD negativity and being able to give these patients years and years of treatment free and ideally, disease-pfree survival.
Irene Ghobrial: Yeah, so you bring up a very good point of toxicity. But also, will that cause harm? Will the clones become resistant later on and with a fixed duration of therapy and potentially leaving them without therapy for a very long time? Whether that will actually lead to if they progress and hopefully they don’t for many, many years. And they are with an amazing quality of life, but even if they progress, they have been off therapy and there is no evidence of clonal selection with long term follow up, although we need still long term follow up of our patients, but maybe an answer is potentially immunotherapy in an earlier setting.

There were lots of discussions today about early detection, risk stratification, early interceptions. Just want to have a sense from you: what are the take home messages?

Omar Nadeem: Yeah, I think there’s clearly a lot of interest in this space, as you can see. There’s a lot of enthusiasm, and I think just learning across all the different disciplines I think has been great. There’s so many similarities between all these precursor hematologic conditions that, you know, you can learn from each other and really take it back and kind of develop the next processes to kind of further fine tune this. But I think the big take home message, again, is identifying the patient population that is going to benefit the most from these therapies and then really figure out what that best therapy is and the right duration and timing.

Kwee Yong: Absolutely no, I agree. I think identifying the right patient population is still a challenge in many areas and perhaps globally as well. Really, if you have a screening strategy, getting that to the right population and the right group of people. And the other big take home message for me is the priority on the part of the patients; it’s what patients want and what patient priorities are. And we need to try and understand that, in order to develop the best way forward and to manage them best, and also to get them to enter studies and take part in our screening trials and our interventional studies.

Irene Ghobrial: Absolutely. The patient voice is the most important voice, not ours, but them. So with that we want to say thank you everyone, thank you both for an amazing meeting in the interception of blood cancer. We look forward to next year and look forward to many other discussions on early detection and interception across blood cancers. Thank you.